5.5.1History

A discussion of toxins ﬁrst necessitates the understanding and distinction between the toxicological terms toxicant and toxin. A toxicant is any chemical, of natural or synthetic origin, capable of causing a deleterious effect on a living organism. Atoxin is a toxicant that is produced by a living organism and is not used as a synonym fortoxicant—alltoxins are toxicants, but not all toxicants are toxins. Toxins, whether produced by animals, plants, insects, or microbes are generally metabolic products that have evolved as defense mechanisms for the purpose of repelling or killing predators or pathogens. The action of natural toxins has long been recognized and understood throughout human history. For example, ancient civilizations used natural toxins for both medicinal (therapeutic) and criminal purposes. Even today, we continue to discover and understand the toxicity of natural products, some for beneﬁcial pharmaceutical or therapeutic purposes whose safety and efﬁcacy are tested, and some for other less laudable purposes like biological or chemical warfare. Toxins may be

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classiﬁed in various ways depending on interest and need, such as by target organ toxicity or mode of action, but are commonly classiﬁed according to source.

5.5.2Microbial Toxins

The term “microbial toxin” is usually reserved by microbiologists for toxic substances produced by microorganisms that are of high molecular weight and have antigenic properties; toxic compounds produced by bacteria that do not ﬁt these criteria are referred to simply as poisons. Many of the former are proteins or mucoproteins and may have a variety of enzymatic properties. They include some of the most toxic substances known, such as tetanus toxin, botulinus toxin, and diphtheria toxin. Bacterial toxins may be extremely toxic to mammals and may affect a variety of organ systems, including the nervous system and the cardiovascular system. A detailed account of their chemical nature and mode of action is beyond the scope of this volume.

The range of poisonous chemicals produced by bacteria is also large. Again, such compounds may also be used for beneﬁcial purposes, for example, the insecticidal properties of Bacillus thuringiensis, due to a toxin, have been utilized in agriculture for some time.

5.5.3Mycotoxins

The range of chemical structures and biologic activity among the broad class of fungal metabolites is large and cannot be summarized brieﬂy. Mycotoxins do not constitute a separate chemical category, and they lack common molecular features.

Mycotoxins of most interest are those found in human food or in the feed of domestic animals. They include the ergot alkaloids produced by Claviceps sp., aﬂatoxins and related compounds produced byAspergillus sp., and the tricothecenes produced by several genera of fungi imperfecti, primarilyFusarium sp.

The ergot alkaloids are known to affect the nervous system and to be vasoconstrictors. Historically they have been implicated in epidemics of both gangrenous and convulsive ergotism (St. Anthony’s ﬁre), although such epidemics no longer occur in humans due to increased knowledge of the cause and to more varied modern diets. Outbreaks of ergotism in livestock do still occur frequently, however. These compounds have also been used as abortifacients. The ergot alkaloids are derivatives of ergotine, the most active being, more speciﬁcally, amides of lysergic acid.

Aﬂatoxins are products of species of the genus Aspergillus, particularlyA ﬂavus, a common fungus found as a contaminant of grain, maize, peanuts, and so on. First implicated in poultry diseases such asTurkey-Xdisease, they were subsequently shown to cause cancer in experimental animals and, from epidemiological studies, in humans. Aﬂatoxin B1, the most toxic of the aﬂatoxins, must be activated enzymatically to exert its carcinogenic effect.

Tricothecenes are a large class of sesquiterpenoid fungal metabolites produced particularly by members of the genera Fusarium andTricoderma. They are frequently acutely toxic, displaying bactericidal, fungicidal, and insecticidal activity, as well as causing various clinical symptoms in mammals, including diarrhea, anorexia, and ataxia. They have been implicated in natural intoxications in both humans and animals, such as Abakabi disease in Japan and Stachybotryotoxicosis in the former USSR, and

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are the center of a continuing controversy concerning their possible use as chemical warfare agents.

Mycotoxins may also be used for beneﬁcial purposes. The mycotoxin avermectin is currently generating considerable interest both as an insecticide and for the control of nematode parasites of domestic animals.

5.5.4Algal Toxins

Algal toxins are broadly deﬁned to represent the array chemicals derived from many species of cyanobacteria (blue-greenbacteria), dinoﬂagellates, and diatoms. The toxins produced by these freshwater and marine organisms often accumulate in ﬁsh and shellﬁsh inhabiting the surrounding waters, causing both human and animal poisonings, as well as overt ﬁsh kills. Unlike many of the microbial toxins, algal toxins are generally heat stable and, therefore, not altered by cooking methods, which increases the likelihood of human exposures and toxicity. Many of the more common algal toxins responsible for human poisonings worldwide are summarized herein.

Amnesic Shellﬁsh Poisoning (ASP) was ﬁrst identiﬁed in 1987 from Prince Edward Island, Canada after four people died from eating contaminated mussels. It is caused by domoic acid produced by several species ofPseudonitzschia diatoms. The main contamination problems include mussels, clams, and crabs of the Paciﬁc Northwest of the United States and Canada.

Paralytic Shellﬁsh Poisoning (PSP) was ﬁrst determined to be a problem in 1942 after three people and many seabirds died from eating shellﬁsh on the west coast of the United States, near the Columbia River. It is caused by the saxitoxin family (saxitoxin+ 18 related compounds) produced by several species ofAlexandrium dinoﬂagellates. The main contamination problems include mussels, clams, crabs, and ﬁsh of the Paciﬁc Northwest and Northeast Atlantic.

Neurotoxic Shellﬁsh Poisoning (NSP) is caused by ared-tideproducer that was ﬁrst identiﬁed in 1880 from Florida, with earlier historical references. It causes sickness in humans lasting several days. NSP is not fatal to humans; however, it is known to kill ﬁsh, invertebrates, seabirds, and marine mammals (e.g., manatees). It is caused by the brevetoxin family (brevetoxin+ 10 related compounds produced by the dinoﬂagellateKarenia brevis a.k.a.Gymnodinium breve. The main contamination problems include oysters, clams, and other ﬁlter feeders of the Gulf of Mexico and southeast Atlantic, including North Carolina.

Diarrheic Shellﬁsh Poisoning (DSP). Human poisonings were ﬁrst identiﬁed in the 1960s. It causes sickness in humans lasting several days but is not fatal. It is caused by chemicals of the okadaic acid family (okadaic acid+ 4 related compounds) produced by several species ofDinophysis dinoﬂagellates. The main contamination problems include mussels, clams, and other bivalves of the cold and warm temperate areas of the Atlantic and Paciﬁc Oceans, mainly in Japan and Europe. Only two cases of DSP have been documented in North America.

Ciguatera Fish Poisoning (CFP) was ﬁrst identiﬁed in 1511, CFP is a tropicalsubtropical seafood poisoning that affects up to 50,000 people each year and is the most often reported foodborne disease of a chemical origin in the United States. Caused by consumption of reef ﬁshes (e.g., grouper, snapper), sickness in

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humans lasts several days to weeks, but the human fatality rate is low. It is caused by the ciguatoxin family (ciguatoxin + 3 or more related compounds) and produced by several species of dinoﬂagellates includingGambierdiscus,Prorocentrum,and Ostreopsis. The main contamination problems include herbivorous tropical reef ﬁsh worldwide.

Cyanobacterial (Blue-GreenBacteria) Toxins. Cyanobacterial poisonings were ﬁrst recognized in the late 1800s. Human poisonings are rare; however, kills of livestock, other mammals, birds, ﬁsh, and aquatic invertebrates are common. It is caused by a variety of biotoxins and cytotoxins, including anatoxin, microcystin, and nodularin produced by several species of cyanobacteria, including Anabaena, Aphanizomenon, Nodularia, Oscillatoria, and Microcystis. The main contamination problems include all eutrophic freshwater rivers, lakes, and streams.

Ambush Predator (Pﬁesteria piscicida and Toxic Pﬁesteria Complex) Toxins. Members belonging to this group of organisms were ﬁrst identiﬁed in 1991 from estuaries in North Carolina. They were believed to produce a toxin that has been implicated in several large ﬁsh kills and is suspect in causing adverse human health effects. However, the toxin or toxins are not yet identiﬁed and toxicity tests are not universally conclusive. Produced by several dinoﬂagellate species including, Pﬁesteria piscicida, Pﬁesteria shumwayae, and perhaps several other unidentiﬁed, un-named dinoﬂagellates belonging to the potentially toxic Pﬁesteriacomplex. Main problems include major ﬁsh kills in North Carolina and Maryland and potential human health problems. The range may extend from the Gulf of Mexico to the Atlantic estuarine waters, including Florida, North Carolina, Maryland, and Delaware, and possibly outward to Europe.

5.5.5Plant Toxins

The large array of toxic chemicals produced by plants (phytotoxins), usually referred to as secondary plant compounds, are often held to have evolved as defense mechanisms against herbivorous animals, particularly insects and mammals. These compounds may be repellent but not particularly toxic, or they may be acutely toxic to a wide range of organisms. They include sulfur compounds, lipids, phenols, alkaloids, glycosides, and many other types of chemicals. Many of the common drugs of abuse such as cocaine, caffeine, nicotine, morphine, and the cannabinoids are plant toxins. Many chemicals that have been shown to be toxic are constituents of plants that form part of the human diet. For example, the carcinogen safrole and related compounds are found in black pepper. Solanine and chaconine, which are cholinesterase inhibitors and possible teratogens, are found in potatoes, and quinines and phenols are widespread in food. Livestock poisoning by plants is still an important veterinary problem in some areas.

5.5.6Animal Toxins

Some species from practically all phyla of animals produce toxins for either offensive or defensive purposes. Some are passively venomous, often following inadvertent ingestion, whereas others are actively venomous, injecting poisons through specially

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adapted stings or mouthparts. It may be more appropriate to refer to the latter group only as venomous and to refer to the former simply as poisonous. The chemistry of animal toxins extends from enzymes and neurotoxic and cardiotoxic peptides and proteins to many small molecules such as biogenic amines, alkaloids, glycosides, terpenes, and others. In many cases the venoms are complex mixtures that include both proteins and small molecules and depend on the interaction of the components for the full expression of their toxic effect. For example, bee venom contains a biogenic amine, histamine, three peptides, and two enzymes (Table 5.5). The venoms and defensive secretions of insects may also contain many relatively simple toxicants or irritants such as formic acid, benzoquinone, and other quinines, or terpenes such as citronellal. Bites and stings from the Hymenoptera (ants, bees, wasps, and hornets) result in 5 to 60 fatal anaphylactic reactions each year in the United States. According to experts, about 0.3% to 3.0% of the US population experiences anaphylactic reactions from insect stings and bites.

Snake venoms have been studied extensively; their effects are due, in general, to toxins that are peptides with 60 to 70 amino acids. These toxins are cardiotoxic or neurotoxic, and their effects are usually accentuated by the phospholipases, peptidases, proteases, and other enzymes present in venoms. These enzymes may affect the bloodclotting mechanisms and damage blood vessels. Snake bites are responsible for less than 10 deaths per year in the United States but many thousand worldwide.

Many ﬁsh species, over 700 species worldwide, are either directly toxic or upon ingestion are poisonous to humans. A classic example is the toxin produced by the puffer ﬁshes (Sphaeroides spp.) called tetrodotoxin (TTX). Tetrodotoxin is concentrated in the gonads, liver, intestine, and skin, and poisonings occurs most frequently in Japan and other Asian countries where the ﬂesh, considered a delicacy, is eaten as “fugu.” Death occurs within 5 to 30 minutes and the fatality rate is about 60%. TTX is an inhibitor of thevoltage-sensitiveNa channel (like saxitoxin); it may also be found in some salamanders and may be bacterial in origin.

Toxins and other natural products generally provide great beneﬁt to society. For example, some of the most widely used drugs and therapeutics like streptomycin, the aminoglycoside antibiotic from soil bacteria, and acetylsalicylic acid (aspirin), the nonsteroidal anti-inﬂammatoryfrom willow tree bark, are used by millions of people everyday to improve health andwell-being.On the other hand, adverse encounters with toxins like ﬁsh and shellﬁsh toxins, plant, and insect toxins do result in harm to humans.